Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study.

Abstract

OBJECTIVE:

Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA.

METHODS:

Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax-IL15. HuMax-IL15 was administered to 30 RA patients who received no other disease-modifying antirheumatic drugs in a 12-week, dose-ascending, placebo-controlled, double-blind, phase I-II proof-of-concept study.

RESULTS:

In vitro studies showed that HuMax-IL15 suppressed proliferation and induced apoptosis in an IL-15-dependent cell line, BDB2, and was capable of suppressing the release of interferon-gamma by synovial fluid mononuclear cell (SFMC) cultures induced by exogenous IL-15. Furthermore, HuMax-IL15 F(ab')2 fragments suppressed exogenous IL-15-induced CD69 expression in RA peripheral blood mononuclear cells and SFMCs, which indicates that HuMax-IL15 can specifically neutralize several biologic effects of IL-15 in synovial tissue in vitro. In a phase I-II clinical trial, HuMax-IL15 was well tolerated clinically, with no significant effects on T lymphocyte subset and natural killer cell numbers. Substantial improvements in disease activity were observed according to the American College of Rheumatology criteria for 20% improvement (63% of patients), 50% improvement (38%), and 70% improvement (25%).

CONCLUSION:

These clinical data suggest for the first time that IL-15 could represent a novel therapeutic target in RA.

• Authors: Bo Baslund, Niels Tvede, Bente Danneskiold-Samsoe, Per Larsson, Gabriel Panayi, Joergen Petersen, Lars J Petersen, Frank J M Beurskens, Janine Schuurman, Jan G J van de Winkel, Paul W H I Parren, J Alastair Gracie, Sarah Jongbloed, Foo Y Liew, Iain B McInnes
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 52 Issue 9 Pg. 2686-92 (Sep 2005) ISSN: 0004-3591 [Print] United States
• PMID: 16142748 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Interleukin-15
• Interferon-gamma

Topics

• Adult
• Aged
• Antibodies, Monoclonal (adverse effects, therapeutic use)
• Apoptosis (drug effects)
• Arthritis, Rheumatoid (drug therapy, physiopathology)
• Cell Death (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Feasibility Studies
• Humans
• Injections, Subcutaneous
• Interferon-gamma (metabolism)
• Interleukin-15 (immunology)
• Killer Cells, Natural (drug effects, pathology)
• Leukocytes, Mononuclear (drug effects, metabolism, pathology)
• Middle Aged
• Severity of Illness Index
• Synovial Fluid (cytology, drug effects, metabolism)
• T-Lymphocyte Subsets (drug effects, pathology)
• Treatment Outcome